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Heart failure (HF) is a global public health burden and associated with significant morbidity and mortality. HF can result as a complication following myocardial infarction (MI), with cardiac fibrosis forming in the myocardium as a response to injury. The dense, avascular scar tissue that develops in the myocardium after injury following MI creates an inhospitable microenvironment that hinders cellular function, survival, and recruitment, thus severely limiting tissue regeneration. We have previously demonstrated the ability of hyaluronic acid (HA) polymer microrods to modulate fibroblast phenotype using discrete biophysical cues and to improve cardiac outcomes after implantation in rodent models of ischemia-reperfusion MI injury. Here, we developed a dual-pronged biochemical and biophysical therapeutic strategy leveraging bioactive microrods to more robustly attenuate cardiac fibrosis after acute myocardial injury. Incorporation of the anti-fibrotic proteoglycan decorin within microrods led to sustained release of decorin over one month in vitro and after implantation, resulted in marked improvement in cardiac function and ventricular remodeling, along with decreased fibrosis and cardiomyocyte hypertrophy. Together, this body of work aims to contribute important knowledge to help develop rationally designed engineered biomaterials that may be used to successfully treat cardiovascular diseases.

The coronavirus disease 2019 (COVID-19) pandemic has greatly impacted healthcare services around the world. Pharmacists are front-line healthcare professionals and integral members of the healthcare team. The deployment of a specialized ‘COVID pharmacist’ within our institution has demonstrated that the skills of the pharmacist can be adapted, expanded and utilized to alleviate the pressure of doctor shortages, reduce healthcare worker exposure to infected patients, contribute to therapeutic decisions and work collaboratively to tackle the challenges faced during this pandemic. This commentary details an Australian hospital pharmacy response to the COVID-19 pandemic, describing the unique clinical and practical contributions made by a specialized COVID pharmacist in our institution.

The role of paclitaxel in the treatment of femoropopliteal peripheral arterial disease is currently ambiguous. A summary-level meta-analysis of randomised trials published in 2018 demonstrated that paclitaxel-coated devices were associated with an increased all-cause mortality in those who underwent treatment at 2 years and 5 years. Further evaluation has been undertaken to establish whether there is a specific dose response, mechanism or reproducible signal. At this time, there has been no confirmation of dose response, as was initially asserted by the summary-level meta-analysis. No mechanism of harm has been identified. Although an association with increased mortality has been confirmed by patient-level meta-analysis, the strength of the signal has been inconsistent. The information suggests there is only an association between paclitaxel-coated devices and increased all-cause mortality, not causation. The authors encourage additional studies designed to follow long-term results after treatment with paclitaxel-coated devices, using real patient data, before a conclusion can be made.

Lack of autonomy in the operating room (OR) during general surgery residency is a major contributing factor to low confidence operating independently after graduation. Although attempts to address decreased autonomy and development of entrustment in the OR are being made in general surgery programs, this issue has not been examined thoroughly in vascular surgery. We sought to determine barriers and opportunities for developing operative autonomy during vascular surgery training by surveying program directors (PDs) and trainees (integrated residents and fellows) in U.S. vascular surgery training programs.An anonymous electronic survey was sent via email to all PDs (n = 155) and trainees (n = 516) in United States vascular surgery training programs. Demographics, academic characteristics, and responses regarding factors impacting the development of entrustment were collected.Thirty-five PDs and 100 trainees completed the survey (22.5% and 19.4% response rate, respectively). Sixty percent of trainees were integrated residents and 40% were fellows. Twenty percent of PDs and 33% of trainees were female, and 5% of all PDs and trainees were from underrepresented minorities. The single most positive factor affecting the development of autonomy according to trainees and PDs is familiarity of the faculty with the trainee. Both PDs and trainees thought the trainee's preparation for the case positively affected development of autonomy; however, more PDs believed that involvement with preoperative preparation in particular (marking the patient, consenting the patient, filling out a history and physical, prepping and draping the patient) was important (P0.05). PDs believed that duty-hour limitations negatively affected the trainee's ability to develop autonomy in the OR, whereas more trainees believed that hospital or OR efficiency policies played a negative role (P0.05). Finally, compared with trainees, PDs believed that the appropriate amount of time for safe struggle before the attending should take over the case was when OR efficiency was compromised or at any moment the trainee is unsure of themselves (P0.05); trainees believed that the attending should take over the case after the limit of their skill set or troubleshooting ability was reached (P0.05).Familiarity of the attending physician with the trainee is an important positive factor for development of entrustment and autonomy in vascular surgery trainees. Duty-hour limitations and belief of the need for hospital efficiency may negatively impact operative independence of trainees. An open discussion about balancing OR efficiency and trainees' safe struggle is essential to address the growth of independent operative skills in vascular surgery trainees.

Mentorship within surgery, particularly vascular surgery, has not been extensively evaluated. This study sought to examine mentorship experiences in graduating vascular trainees (VTs).An anonymous electronic survey examining current mentor relationships, ideal characteristics, academic productivity, and operative comfort level was emailed to all US graduating 2015 (n = 141) and 2016 (n = 144) VTs during their last year of training. A parallel survey was emailed to program/associate program directors (PDs) of all US vascular training programs (n = 169).Surveys were completed by 65 (38%) PDs and 62 (22%) VTs. Forty-three (69%) VTs identified a mentor with no difference in frequency of having a mentor noted among gender, type of training (fellowship/residency), or geographical region. The majority (41/43, 95%) recognized a vascular surgeon as their mentor; the mentor was assigned to 10 of 43 (23%) trainees and was their PD to 9 of 43 (21%). Ideal mentor characteristics, identified by VTs using 4-point Likert scales, were approachability, supportiveness, and accessibility (3.94, 3.76, and 3.74, respectively), while those of a good mentee were enthusiasm, ethical work, and commitment (3.79, 3.69, and 3.45, respectively). Trainees scored accessibility, approachability, compassion, and same gender significantly higher than PDs as characteristics of ideal mentors (P 0.05). The majority of PDs thought mentorship increased access to research opportunities, professional networking, and job opportunities, but not operative skill (90%, 95%, 65%, and 18%, respectively). There was no difference between trainees with mentors and those without in terms of reported academic productivity or operative comfort level. Vascular fellows reported higher comfort than residents in open abdominal aortic aneurysm repair (3.32 vs. 2.73, P = 0.006), juxtarenal aneurysm repair (2.8 vs. 2.1, P = 0.02), and aorto-mesenteric bypass (2.57 vs. 1.93, P = 0.03), and neither group was comfortable performing carotid stenting or fenestrated endovascular aneurysm repairs.There is no difference in academic productivity or case comfort level between surgical trainees with mentors and those without. Possible benefits identified by PDs and trainees include professional networking and increased research and job opportunities. Mentors should be approachable, accessible, supportive, and ethical, while mentees should be enthusiastic, ethical, committed, and approachable. Vascular fellows feel more comfortable with open vascular operations than residents, and nether group feels comfortable with complex endovascular cases. More research is warranted.

ObjectivesThe success of prosthetic vascular grafts in the management of peripheral arterial disease is frequently limited by the development of anastomotic neointimal hyperplasia (ANIH), with the host response to prosthetic grafts beginning soon after implantation. To address this, we combine a platform of polyethylene terephthalate (PET) fabric with an applied cryogel layer containing biologic agents to create a bioactive prosthetic graft system, with the ability to deliver therapeutics targeting modulators of the ANIH-associated transcriptome response, along with antithrombotic agents.MethodsHybrid graft materials were synthesized by cryopolymerization of methacrylated alginate and heparin onto electrospun (ePET), knitted PET (kPET), or woven PET (wPET). Arg-Gly-Asp (RGD) peptides were added to increase cell adhesion. Scanning electron microscopy (SEM) was used to study the microstructure at 1 day, and 2, 4, and 8 weeks. Physical properties such as swelling ratio, pore connectivity, shape recovery, and stiffness were evaluated. Human aortic endothelial cell (HAoEC) adherence was visualized using confocal microscopy after 24 hours and proliferation was evaluated with a resazurin-based assay for 7 days. Confocal microscopy was used to assess delivery of adeno-associated virus (AAV-GFP) after incubation of hybrid grafts with HAoECs. Heparin activity of the materials was measured using an anti-Xa assay.ResultsSEM demonstrated large interconnected pores throughout the entire structure for all graft types, with minimal degradation of the cryogel after 8 weeks. Hybrid materials showed a trend towards increased shape recovery, increased stiffness, decreased swelling ratio, and no difference in pore connectivity. HAoECs incorporated, adhered, and proliferated over 7 days on all materials. HAoECs were successfully transduced with AAV-GFP from the hybrid graft materials. Anti-Xa assay confirmed continued activity of heparin from all materials for over 7 days.ConclusionsWe have developed a bioactive prosthetic graft system with a cryogel coating capable of delivering biologic agents with antithrombotic activity. By applying the cryogel and selected agents onto PET prior to graft implantation, this study sets the stage for the system to be individualized and tailored to the patient, with bioengineering and targeted gene therapy strategies dovetailing to create an improved prosthetic graft adaptable to emerging knowledge and technologies.

In an effort to inhibit the response to vascular injury that leads to intimal hyperplasia, this study investigated the in vivo efficacy of intraluminal delivery of thrombospondin-2 (TSP-2) small interfering RNA (siRNA). Common carotid artery (CCA) balloon angioplasty injury was performed in rats. Immediately after denudation, CCA was transfected intraluminally (15 min) with one of the following: polyethylenimine (PEI)+TSP-2 siRNA, saline, PEI only, or PEI+control siRNA. CCA was analyzed at 24 h or 21 d by using quantitative real-time PCR and immunohistochemistry. TSP-2 gene and protein expression were significantly up-regulated after endothelial denudation at 24 h and 21 d compared with contralateral untreated, nondenuded CCA. Treatment with PEI+TSP-2 siRNA significantly suppressed TSP-2 gene expression (3.1-fold) at 24 h and TSP-2 protein expression, cell proliferation, and collagen deposition up to 21 d. These changes could be attributed to changes in TGF-β and matrix metalloproteinase-9, the downstream effectors of TSP-2. TSP-2 knockdown induced anti-inflammatory M2 macrophage polarization at 21 d; however, it did not significantly affect intima/media ratios. In summary, these data demonstrate effective siRNA transfection of the injured arterial wall and provide a clinically effective and translationally applicable therapeutic strategy that involves nonviral siRNA delivery to ameliorate the response to vascular injury.-Bodewes, T. C. F., Johnson, J. M., Auster, M., Huynh, C., Muralidharan, S., Contreras, M., LoGerfo, F. W., Pradhan-Nabzdyk, L. Intraluminal delivery of thrombospondin-2 small interfering RNA inhibits the vascular response to injury in a rat carotid balloon angioplasty model.

Chronic mesenteric ischemia most commonly occurs secondary to atherosclerotic disease of the mesenteric arteries. Patients are often older than 60 years and can present with postprandial abdominal pain, nausea, diarrhea, and significant weight loss. Symptomatic disease has traditionally been managed with open surgical repair, but endovascular strategies, such as percutaneous angioplasty and stenting, have emerged as the mainstays of therapy. Complications from stenting include plaque embolization, thrombosis, perforation, or dissection of the mesenteric arteries. We present a patient with symptomatic acute aortic dissection 18 months after celiac and superior mesenteric artery stent placement for chronic mesenteric ischemia.

Objectives: Long-term success of prosthetic grafts (PG) in peripheral arterial disease is limited by development of anastomotic neointimal hyperplasia. We have constructed a bioactive prosthetic graft material (BPGM) capable of delivering biologic agents in vitro, and evaluate our BPGM in vivo with a rabbit carotid interposition bypass model. Methods: We synthesized our BPGM by cryopolymerization of RGD with methacrylated alginate and heparin, coating 1.5cm by 2mm electrospun PET (ePET) grafts, and dipcoating in fluorescent siRNA for 3 hours. Three rabbits received bare ePET and 3 received cryogel-coated ePET for a carotid interposition bypass (Figure 1). After 24 hours, bypass patency was assessed, and cell toxicity of the proximal anastomosis, mid-graft, and distal anastomosis examined with H&E staining. Confocal microscopy was used to visualize fluorescence, correlating with ability to deliver siRNA in vivo. Results: Graft patency was equal between groups, with no increased cell toxicity in rabbits receiving cryogel-coated ePET. Confocal microscopy demonstrated no difference in retained fluorescence between rabbits receiving cryogel-coated or bare ePET, and no increased transfection of cells at 24 hours (Figure 2). Conclusion: Creation of the optimal PG demands a material that is biocompatible, responsive, and nonthrombogenic. We have constructed a modified PG capable of in vitro delivery of targeted gene therapies, with comparable patency and biocompatibility in our large animal model. Additional optimization to achieve predictable and sustained release is needed to validate this as an effective and practical method to deliver biologic agents in vivo.

Cobb syndrome is a rare neurocutaneous disorder characterized by spinal vascular abnormalities in association with a vascular lesion of the skin at the same metamere. Patients present after the onset of symptoms such as paraplegia, back pain, and, less commonly, fatigue due to heart failure. Available treatment options to date have included neurosurgical resection and endovascular embolization. We present a patient with Cobb syndrome with a progressively symptomatic arteriovenous malformation involving the thoracic vertebrae and left hemithorax, with extensive blood supply from the T3 to T10 intercostal arteries, and demonstrate successful endovascular thoracic stent graft placement and coil embolization.

Objectives: Anastomotic neo-intimal hyperplasia (ANIH) remains a limiting factor in the long-term success of prosthetic vascular grafts. Understanding of the molecular mechanisms involved in the host response to prosthetic material has set the stage for using this material to deliver siRNA and other modulators of the ANIH-associated transcriptome response, along with antithrombotic agents. To create practical and effective drug delivery from a prosthetic material, we have combined a platform of polyethylene terephthalate (PET) fabric with an applied cryogel carrying the biologic agents, resulting in a bioactive prosthetic graft system (BPGS). Methods: Hybrid grafts were synthesized by cryopolymerization of methacrylated alginate and heparin onto electrospun, knitted, or woven PET. Arg-Gly-Asp peptides were added to increase cell adhesion. Scanning electron microscopy (SEM) was used to study the microstructure at 1 day, and 2, 4, and 8 weeks. Human aortic endothelial cell (HAoEC) adherence and proliferation were assessed with a resazurin-based assay, and confocal microscopy was used to visualize cell interaction with the graft material. Heparin activity of the material in buffer solution was measured using an anti-Xa assay. Results: SEM demonstrated large interconnected pores throughout the entire structure for all graft types, with minimal degradation of the cryogel after 8 weeks. HAoEC incorporated, adhered, and proliferated over 7 days for all materials (Figure 1). Anti-Xa assay confirmed continued activity of heparin from all grafts over 7 days. Conclusion: We have created a BPGS with a biocompatible cryogel polymer coating that allows for cell adherence and growth, with antithrombotic activity. This system allows application of the gel and biologic agents to PET prior to implantation, and provides flexibility in combining bioengineering and targeted gene therapy approaches to create an improved prosthetic graft adaptable to evolving strategies.

The promise of portable diagnostic devices relies on three basic requirements: comparable sensitivity to established platforms, inexpensive manufacturing and cost of operations, and the ability to survive rugged field conditions. Solid state nanopores can meet all these requirements, but to achieve high manufacturing yields at low costs, assays must be tolerant to fabrication imperfections and to nanopore enlargement during operation. This paper presents a model for molecular engineering techniques that meets these goals with the aim of detecting target sequences within DNA. In contrast to methods that require precise geometries, we demonstrate detection using a range of pore geometries. As a result, our assay model tolerates any pore-forming method and in-situ pore enlargement. Using peptide nucleic acid (PNA) probes modified for conjugation with synthetic bulk-adding molecules, pores ranging 15-50 nm in diameter are shown to detect individual PNA-bound DNA. Detection of the CFTRΔF508 gene mutation, a codon deletion responsible for ∼66% of all cystic fibrosis chromosomes, is demonstrated with a 26-36 nm pore size range by using a size-enhanced PNA probe. A mathematical framework for assessing the statistical significance of detection is also presented.

The treatment of cancer has largely relied on killing tumor cells with nonspecific cytotoxic therapies and radiotherapy. This approach, however, has limitations including severe systemic toxicities, bystander effects on normal cells, recurrence of drug-resistant tumor cells, and the inability to target micrometastases or subclinical disease. An increased understanding of the critical role of the immune system in cancer development and progression has led to new treatment strategies using various immunotherapies. It is now recognized that established tumors have numerous mechanisms of suppressing the antitumor immune response including production of inhibitory cytokines, recruitment of immunosuppressive immune cells, and upregulation of coinhibitory receptors known as immune checkpoints. This review focuses on the immune checkpoint inhibitors, a novel class of immunotherapy first approved in 2011. Our objective is to highlight similarities and differences among the three immune checkpoint inhibitors approved by the U.S. Food and Drug Administration-ipilimumab, pembrolizumab, and nivolumab-to facilitate therapeutic decision making. We conducted a review of the published literature and conference proceedings and present a critical appraisal of the clinical evidence supporting their use in the treatment of metastatic melanoma and advanced squamous non-small cell lung cancer (NSCLC). We also compare and contrast their current place in cancer therapy and patterns of immune-related toxicities, and discuss the role of dual immune checkpoint inhibition and strategies for the management of immune-related adverse events. The immune checkpoint inhibitors have demonstrated a dramatic improvement in overall survival in patients with advanced melanoma and squamous NSCLC, along with acceptable toxicity profiles. These agents have a clear role in the first-line treatment of advanced melanoma and in the second-line treatment of advanced squamous NSCLC.

Background Recent studies suggest that axillary lymph node dissection (ALND) may be omitted in select breast cancer patients with a positive sentinel lymph node biopsy (SLNB). As we trend away from ALND, we must understand the burden of axillary disease among various patient subgroups. For patients with positive nodes determined using ultrasound-guided needle biopsy (USNB), there are no data regarding the extent of axillary disease. Patients and Methods An institutional breast cancer registry was retrospectively reviewed to identify women with invasive cancer and a positive USNB/SLNB who had completion ALND. For statistical analysis, we used χ 2 and 1-way analysis of variance. Results One hundred ninety-nine USNB-positive (USNB + ) patients and 434 SLNB + patients were eligible for the study. Positive USNB patients were significantly older, had larger tumors, and were more likely to be estrogen receptor-negative/progesterone receptor-negative and HER2/ neu + than SLNB + patients. USNB + patients had much higher rates of N2 (33.2% vs. 12.4%; P P + patients. Higher axillary disease burden was demonstrated in USNB patients who were clinically node negative and those who met Z11 criteria. Conclusion Patients with invasive breast cancer with a positive node on USNB have a significantly greater burden of axillary disease compared with patients with a positive SLNB. USNB + patients represent a distinct patient population and further research is required to determine if these patients can be safely exempted from axillary dissection.

Chronic mesenteric ischemia most commonly occurs secondary to atherosclerotic disease of the mesenteric arteries. Patients are often older than 60 years and can present with postprandial abdominal pain, nausea, diarrhea, and significant weight loss. Symptomatic disease has traditionally been managed with open surgical repair, but endovascular strategies, such as percutaneous angioplasty and stenting, have emerged as the mainstays of therapy. Complications from stenting include plaque embolization, thrombosis, perforation, or dissection of the mesenteric arteries. We present a patient with symptomatic acute aortic dissection 18 months after celiac and superior mesenteric artery stent placement for chronic mesenteric ischemia.

this study was to quantitatively weigh the risks and benefits of IVC filter retrieval using formal decision analysis. Methods: A Markov state-transition model was used to simulate two clinical scenarios: to leave a previously placed IVC filter or to retrieve it. Analysis was performed over the lifetime of the individual, and outcomes were expressed in quality-adjusted life years (QALYs). The base case is a 60-year-old man with a filter placed within 3 months who no longer requires mechanical thromboprophylaxis. Potential events included PE, filter complications, and death from all other causes during each cycle. Tolls were used to incorporate the disutility of short-term treatment for PE and/or filter complications. For the base-case and sensitivity analyses, we used utilities and probabilities derived from the literature. Results: In the base-case scenario, leaving the filter in place was preferred to filter retrieval, yielding 22.3 vs 21.9 QALYs. One-way sensitivity analysis demonstrated that filter retrieval might be preferable if the utility of living with a filter is

Abstract 3998 Poster Board III-934 Introduction Pulmonary embolism (PE) is a leading cause of morbidity and mortality in the U.S. We and others previously have shown that PE is increasingly detected with increasing use of spiral computerized tomography (CT), at lower severity of illness, suggesting earlier PE diagnosis. Although thrombosis is increased in those with sickle cell trait (Austin, Blood 2007), data are lacking on the prevalence and predictors of PE among individuals with sickle cell disease (SCD), in whom thrombosis may be driven by hemolysis-associated endothelial dysfunction and platelet aggregation. Methods We performed a case-control study to compare demographics, co-morbidity, severity of illness, and mortality in SCD cases with PE and SCD controls without PE, by analyzing statewide discharge data (2001-2006) from the Pennsylvania Health Care Cost Containment Council (PHC4). For this analysis “SCD” included ICD-9 codes for HbSS, HbS/C, HbS/thal, and HbS trait. Clinical and laboratory data were obtained on local SCD cases and controls from the Medical Archival Record System (MARS) at the University of Pittsburgh, using the same ICD-9 codes. Cases were matched by age within 5 years, race, gender, year of admission, and (for PHC4 data only) hospital system. Results The prevalence of PE among SCD admissions, 2001-2006, was 119/ 20,847 (0.57%), increasing over the period by 41.2%, from 0.51% to 0.72%. By comparison, among non-SCD admissions, the prevalence of PE was 66,440/1,416,109 (4.7%), with a similar rate of increase, 54.0%, from 3.78% to 5.82% over the same period. As compared to controls without PE, SCD PE cases had a longer length of stay, 9 vs. 5 days (p=0.0006), greater severity of illness, two highest scores 11.1% vs. 0%, (p=0.0002), and a higher in-hospital mortality rate, 8.7% vs. 0% (p=0.0011). In the local sample (n=14 cases, n=28 controls), the majority of cases were evaluated by spiral CT scans (92.8%). Co-morbidity rates were no greater in cases than controls, including pneumonia (p=0.227), heart failure (p=0.461), coronary symptoms (p=0.464), or stroke (p=0.183). Risk factors for thrombosis were also similar between groups, including estrogen use (p=0.461), obesity (p= 0.763), hyperlipidemia (p=0.106), hypertension (p=0.146), diabetes (p=0.276), smoking (p=0.069), HIV (p=1.000), and HCV (p=0.667). A similar proportion of cases and controls were in crisis, 35.7% each (p=0.888), and there were no differences in the proportion with HbSS, 35.7% vs. 46.4% (p=0.212), HbS/C, 14.3% vs. 0% (p=0.106), HbS/thal, 0% vs. 3.6% (p=0.667), and sickle trait, 50.0% each (p=1.000). Among cases, the degree of anemia (p=0.276), reticulocytosis (p=0.261), WBC (p=0.257) and platelet count (p=0.254) were similar to that of controls. There was no difference between groups in the proportion receiving hydroxyurea (p=0.167), iron chelation therapy (p=1.000), or red cell transfusions (p=0.262). Conclusions Rates of PE are increasing in hospitalized SCD patients in Pennsylvania, with greater severity of illness and higher mortality than in SCD patients without PE. The clinical and laboratory parameters, including severity of hemolysis measured, do not appear to be predictive of PE. Thus, prospective studies are needed to evaluate risk for PE by other markers of disease severity, including tests of platelet activation, tissue factor activity, and hemostatic activation, e.g. thrombospondin, von Willebrand factor, and ADAMTS13. Disclosures: No relevant conflicts of interest to declare.